This application proposes continuation of an integrated clinical and laboratory program to develop chemical modifiers of radiation and chemotherapy. The applicant has established clinical guideline for the safe use of the 2-nitroimidazole hypoxic cell radiosensitizer, SR 2508, with external beam irradiation, developed the use of nitromidazole chemomodifiers, and piloted the use of continuous infusion of sensitizer with brachytherapy. His preliminary data indicate that hypoxic cell sensitizers may improve treatment outcome for prostate cancer and may substantially enhance the efficacy of interstitial irradiation. Based on clinical results and important biological concepts, he will conduct clinical trials to assess the efficacy of SR2508 1) With radiotherapy in cancer of the prostate, 2) With chemotherapy and radiation in locally advanced cancers of the esophagus and bladder, 3) With external beam and implanted radiation in cancers of the breast and brain, and 4) as a chemosensitizer in multiple myeloma. When the glutathione-depleting agent, L-BSO, becomes available, he will conduct a clinical trial to deplete glutathione in conjunction with radiation therapy. His laboratory will continue to provide pharmacologic support for the Joint Center for Radiation Therapy and the Radiotherapy Oncology Group trials. The basic laboratory program is directed toward developing novel clinical strategies for overcoming treatment resistance of hypoxic cells, with particular emphasis on the consequences of intermittent hypoxia. Ongoing studies include: 1) the use of a fractionated radiotherapy tumor model to study hypoxia in vivo; 2) investigation of hypoxic cell populations using image analysis with Hoechst 33342 and chromomycin A3, in vitro model systems ("sandwich" and regulated gas diffusion), and intrinsic cellular markers (stress protein patterns), and 3) application of an in vitro assay to study mechanisms of drug-induced neurotoxicity and strategies for preventing or ameliorating the neuropathy associated with SR 2508.